In the human circulatory system, blood first goes to the lungs for oxygenation before being directed to the rest of the body. When the lungs do not function properly, such as for a patient with Respiratory Distress Syndrome (RDS), collapsing of the lungs often requires the use of a ventilator to provide proper respiration. It is known to utilize liquid ventilation systems for pulmonary recruitment and conditioning to treat pulmonary disorders or disease such as RDS. Procedures using liquid ventilation are sometimes referred to as “liquid assisted ventilation” (LAV) procedures. In a LAV procedure, a breathable liquid is instilled into the patient's pulmonary system (e.g., lungs), typically via the patient's trachea, to replace the nitrogen gas that otherwise is the means for carrying oxygen and carbon dioxide during respiration.
Despite significant advances in respiratory care and reduction in mortality of patients with respiratory failure, morbidity persists and often results from iatrogenic mechanisms. In particular, preterm infants weighing less than approximately 1500 gm experience significant acute and chronic respiratory complications. More importantly, during an era of increasing multiple births secondary to infertility management, a greater number of very low birth weight and very preterm infants are born. Those infants weighing less than approximately 500 gm who survive the initial respiratory syndrome of prematurity, commonly (i.e., approximately 85%) experience significant chronic lung disease with neurodevelopmental delay. In this regard, these fragile infants represent an underserved population with respect to existing respiratory therapies.
LAV procedures present a promising modality in the treatment of respiratory distress for both an immature lung or an injured mature lung. It has been found that LAV may confer a cytoprotective benefit to the lung, either by a serving as a mechanical barrier or by direct cytoprotective action. LAV has been associated with a reduction in the number of, as well as the amount of, mediators released by pulmonary inflammatory cells. Mechanisms for cytoprotection may be related to the mechanical reduction of intercellular surface tension, perfluorochemical (“PFC”) miscibility in lipid membranes, cellular PFC ingestion, as well as PFC effect on intercellular adhesions molecules. As such, LAV appears to provide both mechanical and anti-inflammatory protection.
The terms “breathable fluid” and “breathable liquid” both refer to a liquid (i.e., a non-gas) having the ability to deliver oxygen into, and to remove carbon dioxide from, the pulmonary system of a patient. Examples of breathable liquids include, but are not limited to, saline, silicone and vegetable oils, perfluorochemicals (“PFC”), and the like. Presently, PFC liquids are preferred, particularly perfluorocarbon liquids. PFC liquids are clear, colorless, odorless, nonflammable, and essentially insoluble in water. PFC liquids have an extremely high affinity for gases making them very desirable as the means for delivering oxygen to a patient and returning carbon dioxide from the patient. They have low surface tension and, for the most part, low viscosity. They also have anti-oxidative properties and exhibit anti-inflammatory characteristics.
Beneficial uses for PFC liquids in a LAV procedure are numerous. They include: (1) improved gas exchange; (2) opening of atelectatic areas by recruitment to increase total lung capacity; (3) acting as a surfactant to open a collapsed alveoli; (4) acting as a vehicle to deliver biological or non-biological agents; (5) homogenously expanding lung to decrease the risk of overexpansion or underexpansion; (6) removal of debris; (7) decreasing risk of oxygen toxicity; (8) decreasing inflammation in the lung; and (9) increasing pulmonary blood flow to an injured lung area creating better oxygenation. In addition, pulmonary debris (i.e. exudate, meconium, mucous) is readily moved by tidal PFC volumes.
Due to low surface tension, high respiratory gas solubility, and high spreading coefficients of the PFC liquid, the placement of the PFC liquid into the patient's pulmonary system replaces the normally gas-liquid interface with a liquid-liquid interface having low interfacial tension at the lung surface. The PFC liquid also supports an adequate alveolar reservoir for the pulmonary gas exchange. As a result of the reduced interfacial tensions at the lung surface, transmural pressures across the alveolar-capillary membrane are more evenly matched in the liquid-filled lung compared to a gas-filled lung. This promotes more homogeneous pulmonary blood flow in the liquid-filled lung. The addition of a surfactant to the PFC liquid may further reduce collapsing pressures in the PFC-treated lung by further decreasing tension at the PFC-lung interface.
It is also known to use PFC liquid during a LAV procedure as a means of delivering a drug or biologic agent into the lung parenchyma instead of delivering the drug intravenously. Most drugs administered intravenously for a respiratory target enter the lung tissue by passive diffusion. However, such passive diffusion of the drug depends upon the free plasma drug concentration in the pulmonary capillaries, which is often inadequate in the case of a patient with an impaired lung. Lung tissue uptake of an intravenously administered drug also depends upon the ratio of the surface area of the diffusion membranes (i.e., the capillaries) to the extravascular fluid volume in the lung. This ratio, however, is typically low for a patient with an injured lung, thus impairing the uptake of the drug for such a patient.
The above-described properties of PFC liquids also make PFC liquids desirable for intratracheal administration of a drug. Respiratory gas solubility of the PFC liquid supports gas exchange, while the low surface tension and ability to recruit lung volume also allows for drug distribution to the under-ventilated lung regions. Additionally, the inert nature of the PFC liquid precludes any drug-vehicle interactions. When drugs are suspended in the PFC liquid and delivered during tidal liquid ventilation (TLV), it is possible to control the delivery rate, the time of injection, and the total amount of drug delivered to the lung. Thus, intratracheal drug administration during LAV desirably targets the lung compared to an intravenous administration.
Known LAV techniques include total liquid ventilation (TLV), partial liquid ventilation (PLV), PFC-lavage, and aerosol-PFC. In a TLV technique, transport of the respiratory gases is achieved solely in dissolved form through the tidal volume exchange of the PFC liquid to and from the lung. As such, a total liquid ventilation procedure is sometimes also referred to as “tidal liquid ventilation.” As discussed above, all of the gas-liquid interfacial tension is desirably eliminated in TLV. Lung volume is recruited and compliance is increased in TLV while inflation pressures and pulmonary barotrauma are reduced.
In a PLV technique, the lung is instilled and maintained with a functional residual capacity (FRC) of the PFC liquid while mechanical gas ventilation is being performed. In this way, a PLV technique utilizes the alveolar recruitment capabilities of the low surface tension PFC liquid to establish an adequate FRC in an impaired lung. The simultaneous mechanical gas ventilation provides for the exchange of CO2 and oxygen in the lung. Effective ventilation of a lung using PLV is more challenging than TLV because of the increased number of unknown factors in the lung only partially filled with liquid. These unknown factors relate to the distribution of the PFC liquid in the lung, the saturation of oxygen and carbon dioxide in the resident PFC, the continually changing lung mechanics, the evaporative loss of PFC, and the changing volumes of gas and PFC volumes in the lung.
Maintenance of a therapeutic PFC liquid volume following initial instillation in the lungs is dependent upon a number of factors. PFC liquids with different physicochemical properties such as kinematic viscosity, spreading coefficients and CO2 solubility demonstrate diverse patterns of distribution and elimination. For example, a liquid with higher kinematic viscosity tends to distribute less homogeneously but also resists redistribution over time, and thus maintains greater contact with the inspired gas and eliminates relatively faster than a liquid of lower kinematic viscosity and comparable vapor pressure. Liquids of higher vapor pressure will volatize into the expired gas more rapidly than lower vapor pressure liquids. PFC liquid volume loss and evaporation rate from the lungs is influenced by many factors including time, PFC vapor pressure, gas to liquid contact, ventilation strategy, lung pathophysiology, repositioning of the subject, and the administration of supplemental PFC doses to the lungs. It has been found that additional instrumentation is necessary during PLV in order to determine evaporative loss, to guide and sustain dosing levels, and to reduce dose consumption. Also, pulmonary debris will tend to migrate from the distal to proximal lung during PLV. Frequent suctioning to remove debris, therefore, is needed during a PLV procedure.
In a lavage procedure, a liquid (i.e., a PFC liquid) is used to wash out an organ. Thus, in a LAV procedure utilizing PFC-lavage, a PFC liquid is used to wash out the lung. PFC-lavage techniques can also be used for other purposes such as heat transfer to heat or cool a patient. In an aerosol-PFC procedure, the PFC liquid is in an aerosolized form. The aerosolized PFC is typically instilled into the patient via an introducible jet-nebulizer.
Examples of liquid ventilation systems are disclosed in U.S. Pat. No. 5,158,536 (see FIGS. 29 and 34) and U.S. Pat. No. 6,105,572 (see FIGS. 1 and 2). As shown, the liquid ventilation systems are closed-circuit systems because the PFC liquid is circulated in cyclic fashion between the patient and a storage reservoir or regenerator. As described in the '572 patent, expired PFC liquid from the patient is conditioned (i.e., regenerated) in the closed-circuit before being returned to the patient in a subsequent cycle primarily by removing carbon dioxide from, and adding oxygen to, the PFC liquid. The PFC liquid may also be conditioned to adjust temperature or to condense fluorocarbon vapors generated during a therapeutic procedure as a means of conservation.